REVIEW ARTICLE

published: 12 January 2012

doi: 10.3389/fimmu.2011.00098

Chronic inflammation in cancer development

Gabriele Multhoff 1,2 *, Michael Molls 1 and Jürgen Radons 3
1
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
2
Clinical Cooperation Group Innate Immunity in Tumor Biology, Helmholtz Zentrum München, Munich, Germany
3
multimmune GmbH, Munich, Germany

Edited by:
Cristina Bonorino, Pontificia
Universidade Catolica do Rio Grande
do Sul, Brazil
Reviewed by:
Lidija Klampfer, Montefiore Medical
Center and Albert Einstein Cancer
Center, USA
Ana Paula Souza, Pontificia
Universidade Católica do Rio Grande
do Sul, Brazil
*Correspondence:
Gabriele Multhoff , Department of
Radiation Oncology, Klinikum rechts
der Isar, Technische Universität
München, Ismaningerstr. 22, D-81675
Munich, Germany.
e-mail: gabriele.multhoff@lrz.
tu-muenchen.de
Chronic inflammatory mediators exert pleiotropic effects in the development of cancer.
On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor
growth, invasion, and metastatic spread; on the other hand inflammation can stimulate
immune effector mechanisms that might limit tumor growth. The link between cancer and
inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the
activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of
tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple
levels and thereby boost tumor-associated inflammation which can suppress anti-tumor
immune responses. These factors also promote tumor growth, progression, and metasta-
tic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by
modulating the expression of tumor-promoting factors. In this review we concentrate on
the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and
outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual
roles of stress proteins as danger signals in the development of anti-cancer immunity and
anti-apoptotic functions.
Keywords: inflammation, carcinogenesis, tumorigenic factors, heat shock proteins, NF-κB, STAT-3, IL-1

INTRODUCTION an activation of pattern recognition receptors (PRR) that inter-

Based on the presence of leukocytes in cancerous lesions, Rudolf
Virchow, the founder of cellular pathology, speculated about an
association between chronic inflammation and development of
cancer already in 1863 (Virchow, 1863). In line with this observa-
tion, epidemiological studies indicate that apart from hereditary
predisposition, inflammation serves as a potential risk factor for
the development of cancer. Nowadays it is generally accepted
that up to 25% of human malignancies are related to chronic
inflammation and to viral and bacterial infections (Hussain and
Harris, 2007). Table 1 provides an overview on inflammatory and
pathogenic conditions that are considered to be associated with
malignant transformation.
Cancer-related chronic inflammation facilitates unlimited
replicative potential, independence of growth factors, resistance
to growth inhibition, escape of programmed cell death, enhanced
angiogenesis, tumor extravasation, and metastasis (Hanahan and
Weinberg, 2000). Cancer-related inflammation represents the sev-
enth hallmark in the development of cancer (Colotta et al., 2009).
Persistent microbial infections induced by parasites, bacteria, and
viruses and physical and/or chemical stimuli can cause inflam-
mation (Coussens and Werb, 2002). Bacterial infections follow-
ing surgical removal of primary tumors can promote metastatic
growth in mice (Pidgeon et al., 1999) and humans (Taketomi
et al., 1997). This process is mediated most likely by endotoxins
altering the critical balance between cell growth and angiogenesis
(Pidgeon et al., 1999). Moreover, chronic inflammation induced
by non-infectious agents can also contribute to carcinogenesis
and act as a driving force in tumor development. Apart from
toxins, oncoproteins and growth factors can affect the host via
act with pathogen-associated molecular patterns (PAMP). These
receptors comprise to members of the Toll-like receptor (TLR)
family, nucleotide-binding oligomerization domain-like (NOD-
like) receptors (NLR), C-type lectin receptors (CLR), triggering
receptors on myeloid cells (TREM), and retinoic acid inducible
gene-I-like receptors (RLR; Kawai and Akira, 2011). Binding of
PAMP to these receptors leads to an initiation of the host’s immune
response by activation of inflammatory cells. The engagement of
PRR triggers the induction of intracellular signaling pathways that
induce the activation of numerous transcription factors such as
NF-κB, STAT, and FOXO. These factors regulate the expression
of several genes involved in the innate and adaptive immunity
(Akira et al., 2006; Karin et al., 2006). Inadequate pathogen eradi-
cation, recurring tissue injury, prolonged inflammatory signaling,
and failure of anti-inflammatory mechanisms can cause chronic
inflammation which as a result supports tumorigenesis.
IMPACT OF INFLAMMATION IN TUMORIGENESIS
Numerous studies provide evidence that chronic inflammation
increases the risk of cancer, promotes tumor progression, and
supports metastatic spread (Mantovani et al., 2008; Aggarwal
and Gehlot, 2009). In the initial phase of tumor development,
inflammatory mediators such as cytokines, reactive oxygen species
(ROS), and reactive nitrogen species (RNS) derived from tumor-
infiltrating immune cells induce epigenetic alterations in pre-
malignant lesions and silence tumor suppressor genes (Griven-
nikov and Karin, 2010). During tumor promotion, immune cells
secrete cytokines and chemokines that act as survival and prolifera-
tion factors for malignant cells. The angiogenic switch is critical for

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Multhoff et al. Inflammation and cancer

Table 1 | Inflammation and their related cancers. that result in the formation of pro-inflammatory factors including
chemokines, cytokines, and PGHS-2. These molecules recruit and
Inductor Inflammation Cancer activate various leukocyte populations such as macrophages, mast
cells, eosinophils, and neutrophils into the tumor microenviron-
Gut pathogens Inflammatory Colorectal cancer
ment like stromal and endothelial cells as well as infiltrating cells.
bowel disease
This concerted action of tumor and micromilieu results in a more
Tobacco smoke Bronchitis Bronchial lung cancer
pronounced generation of inflammatory mediators that drives the
Helicobacter pylori Gastritis Gastric cancer
progression of a positive amplification loop which further triggers
Human papilloma virus Cervicitis Cervical cancer
tumor growth and invasiveness.
Hepatitic B/C virus Hepatitis Hepatocellular
Proto-oncogene activation represents a critical component in
carcinoma
the intrinsic pathway of cancer-related inflammation. In this con-
Bacteria, gall bladder stones Cholecystitis Gall bladder cancer
text, mutations in RAS genes play an important role in tumori-
Tobacco, genetics, alcohol Pancreatitis Pancreatic cancer
genesis. Overall, up to 30% of all human tumors harbor muta-
Epstein-Barr virus Mononucleosis Burkitt’s lymphoma
tions in canonical RAS genes (KRAS, HRAS, NRAS). Remarkably,
Ultraviolet light Sunburn Melanoma
these oncogenic mutations predominantly affect the KRAS locus,
Asbestos fibers Asbestosis Mesothelioma
with oncogenic KRAS mutations being detected in 25–30% of
Gram-uropathogens Schistosomiasis Bladder cancer
all screened tumor samples (Forbes et al., 2011). The high fre-
(Bilharzia)
quency of KRAS mutations and their appearance in early tumor
Gastric acid, alcohol, tobacco Esophagitis Esophageal
stages argue for a causative role of the K-Ras protein in human
adenocarcinoma
tumorigenesis (Fernandez-Medarde and Santos, 2011). More than
30 years ago the founding members of the RAS gene superfamily
an adequate supply of tumor cells with oxygen, nutrition, growth, (HRAS, NRAS, KRAS) were discovered in human tumors as the
and survival factors (Zumsteg and Christofori, 2009). During first proto-oncogenes. Members of the RAS family are crucial for
tumor progression and metastasis, both tumor and immune cells the connection of up-stream signals to down-stream effector path-
produce cytokines and chemokines leading to an increase in ways that are functionally related to cell cycle progression, growth,
cell survival, motility, and invasiveness (DeNardo et al., 2008). migration, cytoskeletal changes, apoptosis, and senescence. In
Epithelial–mesenchymal transition (EMT), a crucial process in tumor cells, activation of mutated RAS is followed by the induc-
tumor invasiveness and metastasis, is also promoted (Yang and tion of several intracellular signaling pathways. Signaling cascades
Weinberg, 2008). EMT refers to the loss of carcinoma epithelial induced by mutated RAS comprise the RAF/MEK/ERK kinase cas-
phenotype and the acquisition of mesenchymal features (Zeis- cade, the PI3K/AKT pathway, and RalGDS proteins (Downward,
berg and Neilson, 2009). The group of Mehta recently found that 2009), the latter belonging to the family of nucleotide-exchange
aberrant tissue transglutaminase (TG2) expression induces EMT factors activating small GTPases such as RalB. Via the exocyst
in epithelial cells (Kumar et al., 2010). This finding, in conjunc- complex, an octameric protein complex implicated in tethering
tion with the observation that inflammatory signals (e.g., TGF-β, of vesicles to membranes (Yamashita et al., 2010), RalB stim-
TNF, and NF-κB) which induce EMT, also induce TG2 expres- ulates the TANK-binding kinase-1 (TBK-1) resulting in NF-κB
sion (Kawata et al., 2011), suggests a possible link between TG2, activation by IκBα phosphorylation. In cancer cells, a constitutive
inflammation, and cancer progression presumably yielding novel activation of this pathway, via chronic RalB activation, restricts the
therapeutic targets for improved patient outcomes. Other typical initiation of apoptosis after oncogenic stress (Chien et al., 2006).
markers of EMT are cadherin-11 and fibroblast-specific protein Beside NF-κB activation, TBK-1 activates the transcription factors
(FSP)-1 which are associated with an increased motility (Zeisberg IRF-3 and IRF-7 (Hacker and Karin, 2006) leading to the pro-
and Neilson, 2009). Twist is necessary to repress the transcription duction of growth and inflammatory mediators. Previously it has
of E-cadherin (Thiery et al., 2009; Zeisberg and Neilson, 2009). been shown that K-Ras is a direct inducer of pro-inflammatory
IL-6 and pro-angiogenic IL-8 required for the initiation of tumor-
PATHWAYS CONNECTING INFLAMMATION AND CANCER associated inflammation and neovascularization and promoting
According to Mantovani et al. (2008), the connection between tumor growth. In these studies knock-down of IL6, genetic abla-
tumorigenesis and inflammation is mediated via intrinsic and tion of the IL6 gene, or treatment with a neutralizing IL-6 antibody
extrinsic pathways. The intrinsic pathway is activated by genetic retarded K-Ras-driven tumorigenesis (Ancrile et al., 2007). Over-
alterations causing inflammation and neoplasia. These alterations expression of oncogenic K-Ras in tumorigenic HeLa cells induced
comprise mutation-driven proto-oncogene activation, chromo- IL-8 secretion, while IL-8 inhibition reduced growth of these cells
somal rearrangement/amplification, and inactivation of tumor and the number of CD31+ cells in a xenograft tumor model (Spar-
suppressor genes. Transformed cells secrete inflammatory media- mann and Bar-Sagi, 2004). Moreover, TBK-1 and NF-κB signaling
tors and thus generate an inflammatory microenvironment. The have been identified as being essential in K-Ras mutant tumors
extrinsic pathway is driven by inflammation or infections that (Barbie et al., 2009). Regarding these observations it was assumed
increase the risk for the development of cancer in organs at that targeting the NF-κB signaling pathway might be effective in
risk such as the prostate, pancreas, colon, lung, and skin. Both treating RAS-mutated tumors (Downward, 2009). Meylan et al.
pathways interfere in tumor cells and induce the activation of (2009) demonstrated that inhibition of the NF-κB pathway in lung
several transcription factors such as NF-κB, STAT-3, and HIF-1 tumors resulted in significantly reduced tumor growth.

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Multhoff et al.
CRITICAL MOLECULES IN CANCER-RELATED INFLAMMATION
Tumor-associated inflammation requires the presence and acti-
vation of inflammatory cells such as macrophages and granulo-
cytes in the tumor microenvironment, formation of inflamma-
tory mediators by tumor and stromal cells, tumor remodeling,
and angiogenesis (Kundu and Surh, 2008; Colotta et al., 2009).
Accumulation of microbial pathogens and tissue necrosis acti-
vate transcription factors that are necessary for the expression
of, e.g., pro-angiogenic factors (IL-8, VEGF), growth factors (IL-
6, GM-CSF), anti-apoptotic factors (Bcl-XL , c-FLIP), invasion-
promoting factors (MMP-2, MMP-7, MMP-9, uPA), inflamma-
tory enzymes (PGHS-2, LOX), prostaglandins, iNOS, chemokines
(CCL2, CCL20, IL-8), and pro-inflammatory cytokines (IL-1, IL-6,
IL-23, TNF, TGF-β, EGF) that support the malignant phenotype.
All molecules mentioned above are regulated by the transcription
factor NF-κB, a key orchestrator in innate immunity and inflam-
mation that has emerged as a crucial tumor promoter (Karin,
2006). The presence of constitutively active NF-κB was found to be
associated with poor clinical outcome (for an overview see Aggar-
wal and Gehlot, 2009). NF-κB activation in inflammatory cells
in response to infectious pathogens, pro-inflammatory mediators
as well as necrotic cell products results in the generation of sec-
retable factors that support growth, survival, and vascularization
of pre-malignant and malignant cells (Karin, 2006). Activation
of NF-κB up-regulates cell cycle mediators (cyclin D1, c-Myc),
anti-apoptotic (c-FLIP, survivin, Bcl-XL ) and adhesion molecules
(ICAM-1, ELAM-1, VCAM-17), proteolytic enzymes (e.g., MMP,
uPA), and pro-inflammatory factors (PGHS-2, cytokines) that
promote an invasive phenotype (Aggarwal and Gehlot, 2009).
iNOS is another important inflammatory mediator that causes
the production of NO by macrophages that links chronic inflam-
mation and tumorigenesis. Elevated levels of NO have been found
in numerous pre-cancerous and malignant lesions such as Bar-
rett’s mucosa (Wilson et al., 1998), prostate cancer (Aaltoma et al.,
2001), breast cancer (De Paepe et al., 2002), and gastrointestinal
carcinomas (Wink et al., 1998; Jaiswal et al., 2001). The iNOS prod-
uct NO contributes to inflammation-associated tumorigenesis by
inducing DNA damage, suppression of DNA repair, modification
of oncoproteins, inhibition of apoptosis, promotion of tumor
growth, angiogenesis, and metastasis as well as suppression of
anti-tumor immunity (De Paepe et al., 2002). The NO-mediated
inhibition of DNA repair enables cells harboring epigenetic alter-
ations to escape from apoptosis. This results in clonal expansion
of pre-malignant cells and subsequently to carcinogenesis (Sawa
and Ohshima, 2006). Furthermore, NO promotes tumor growth
by a transactivation of HIF-1α (Sandau et al., 2000), induces the
expression of pro-angiogenic VEGF (Ravi et al., 2000), and down-
regulates the tumor suppressor protein p53 (Ambs et al., 1998).
RANKL
RANKL, a member of the TNF superfamily of cytokines, was
originally found in T and dendritic cells (DC). RANKL supports
differentiation and survival of effector cells (Anderson et al., 1997).
Moreover, it is essential for the differentiation of bone-resorbing
osteoclasts derived from monocyte–macrophage precursors, and
enables survival and function of mature osteoclasts (Li et al., 2000;
Teitelbaum, 2000). Recent studies documented an expression of
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Inflammation and cancer
RANKL in a variety of other cell types, including tumor cells.
Breast cancer cells are able to produce RANKL (Park et al., 2003;
Cross et al., 2006) and stimulate osteoclast differentiation when co-
cultured with bone marrow stromal cells (Park et al., 2003). HIF-
1α-induced expression of RANKL initiates an increased migration
of breast cancer cells via the PI3K/AKT pathway (Tang et al., 2011).
The expression of RANKL in prostate cancer cells was found
to be associated with an increased appearance of bone metas-
tases (Brown et al., 2001; Chen et al., 2006). In head and neck
squamous cell carcinoma RANKL expression promotes EMT and
tumor progression by inducing VEGF-independent angiogenesis
(Yamada et al., 2011). Moreover, the activity of RANKL was found
to be involved in the pathophysiology of osteosarcoma (Mori et al.,
2007a,b), giant cell tumors of the bone (Ng et al., 2010), Paget’s
sarcomas (Sun et al., 2006), and vascular diseases (Hofbauer and
Schoppet, 2004). The expression of RANKL increases in response
to pro-inflammatory mediators, such as IL-1 (Fernandez et al.,
2010; Jurado et al., 2010). In fibroblast-like synoviocytes, murine
osteoblastic, and fibroblastic cells, IL-23 was found to induce an
up-regulation of RANKL via STAT-3 and NF-κB signaling path-
ways (Li et al., 2010; Mori et al., 2011). An exposure of these cells to
pro-inflammatory cytokines such as IL-1, TNF, and IL-6 resulted
into a direct or indirect activation of STAT-3 in a feed-forward
loop. Further evidence for a crucial role of STAT-3 in the regula-
tion of RANKL is shown by Schulze et al. (2010) who found that
osteolytic prostate cancer cells induce the expression of RANKL
in a STAT-3/5-dependent manner. Together these data highlight
the significance of a STAT-3/5-mediated cytokine production in
tumor cell migration and the formation of distant metastases.
IL-1 AND TNF
Elevated levels of IL-1 have been identified in several human
tumor entities such as melanoma, head and neck, colon, lung, and
breast cancer. Overall, patients harboring IL-1-positive tumors
have markedly worse prognoses (Lewis et al., 2006). Due to its
pleiotropic nature, IL-1 promotes tumor growth and metastasis
in an autocrine/paracrine manner. IL-1 is produced by tumor,
stromal and endothelial cells, and the host’s infiltrating immune
cells (Lewis et al., 2006). Depending on its subcellular location,
different IL-1 isoforms mediate different functions. Membrane-
bound IL-1α which is expressed on malignant cells induces anti-
tumor immune responses, whereas, intracellular residing precur-
sors of IL-1α control homeostatic functions including gene expres-
sion, differentiation, and cell growth. In contrast, low concen-
trations of secreted IL-1β down-regulate inflammatory responses
and immune mechanisms, whereas high concentrations promote
inflammation-associated tissue damage and tumor invasiveness
(Apte et al., 2006). IL-1 can stimulate other cell types to pro-
duce pro-angiogenic and pro-metastatic mediators and thus plays
an important role in inflammation-associated carcinogenesis (Lin
and Karin, 2007; Voronov et al., 2007). In pancreatic cancer IL-1
confers chemoresistance via an up-regulation of PGHS-2 (Angst
et al., 2008) and promotes angiogenesis during tumor progression
(Shchors et al., 2006).
IL-1α and IL-1β exert identical agonist actions by binding to the
IL-1 receptor type I (IL-1RI). After ligation, IL-1/IL-1RI associates
with the IL-1 receptor accessory protein (IL-1RAcP) leading to
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Multhoff et al.
activation of intracellular signal transduction cascades. This com-
plex recruits a number of intracellular adapter molecules including
MyD88 (Watters et al., 2007; Gay et al., 2011) to activate signal
transduction pathways such as AP-1, p38MAPK, JNK, and NF-
κB (Figure 1). In particular NF-κB provides a mechanistic link
between inflammation and tumorigenesis. NF-κB is a major fac-
tor which controls apoptosis-based tumor immune surveillance
mechanisms of pre-neoplastic and malignant cells. NF-κB also reg-
ulates tumor angiogenesis and invasiveness (Karin, 2006), and may
contribute to chemoresistance of tumor cells (Fahy et al., 2004).
A detailed description of the IL-1 signaling pathway is visualized
schematically in Figure 1.
A third ligand, the naturally occurring IL-1 receptor antagonist
(IL-1Ra), also binds to IL-1RI and acts as a true receptor antag-
onist. Because of its collagenase and prostaglandin-inhibiting
properties, IL-1Ra (anakinra™) is approved for the treatment
of chronic inflammatory diseases including rheumatoid arthritis
(Dinarello, 1996) and systemic onset juvenile idiopathic arthri-
tis (Hedrich et al., 2011). It has also been identified as being
powerful in reverting IL-1 effects in numerous pathological set-
tings (Dinarello, 1996). Actually, anakinra was successfully used
in treating the rare lymphoproliferative disorder Castleman’s dis-
ease (El-Osta et al., 2010) as well as in myeloma (Lust et al., 2009)
rendering the use of anakinra and other IL-1-blocking agents such
as canakinumab™(anti-IL-1β antibody) or rilonacept™(construct
of the two extracellular chains of IL-1RI/IL-1RAcP complex fused
to the Fc segment of IgG) promising therapeutic approaches in
human metastatic diseases. The last two agents have been approved
for the treatment of the cryopyrin-associated periodic syndrome
(CAPS; Hoffman et al., 2008; Lachmann et al., 2009a), a group-
ing of familial cold auto-inflammatory syndrome, Muckle–Wells
syndrome, and neonatal onset multi-inflammatory disease. As
summarized by Dinarello (2010), there are two meaningful reasons
for the use of IL-1-blocking agents in the treatment of metastatic
diseases. On the one hand, none of the above mentioned agents
have been found as being associated with any organ toxicities,
gastrointestinal, or hematological abnormalities. On the other
hand, unlike TNF-blocking agents IL-1-inhibiting treatments lack
opportunistic infections although routine bacterial and upper air-
way infections are observed. Due to the safety of IL-1 blockage
and the availability of the three therapeutics in limiting IL-1
actions, clinical trials are encouraged. An NIH trial of anakinra
in the treatment of cutaneous melanoma is ongoing because IL-
1 plays a pivotal role in angiogenesis by inducing/up-regulating
pro-angiogenic IL-8 and VEGF contributing to the pathogenesis
of, e.g., multiple melanoma (Dinarello, 2010).
As a pleiotropic cytokine, IL-1 harbors numerous intensify-
ing effects on the physiological functions of diverse innate and
immunocompetent cells (Mizel, 1982), IL-12-mediated induction
of Th1 development (Weaver et al., 1988), and induction of Th17
cells (Sutton et al., 2006). IL-1 effects on immune tolerance are also
reported (Nakata et al., 1995). For instance, IL-1β stimulates func-
tion of memory T cells and impairs that of Treg cells (O’Sullivan
et al., 2006). This brief overview highlights the complexity of the
mechanisms by which IL-1 regulates all types of immune responses
including tumor cell eradication.
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Inflammation and cancer
IL-1β is first synthesized as biologically inactive precursor (pro-
IL-1β) that is further processed by caspase-1, also known as IL-1-
converting enzyme (ICE), to the mature form, while pro-IL-1α
is cleaved by calpain. Although IL-1β contributes to growth and
metastatic spread in experimental and human cancers, the mol-
ecular mechanisms regulating the conversion of pro-IL-1β to the
secreted and active cytokine remains to be elucidated.
An elaborate multi-protein complex, the so-called “inflamma-
some,” is responsible for the recruitment and activation of caspase-
1 (Martinon et al., 2002). Each inflammasome consists of different
members of the nucleotide oligomerization domain-like receptor
(NLR) family of proteins. Two of the best characterized human
inflammasomes are NALP (NACHT, LRR, and pyrin domain-
containing protein) 1 inflammasome and NALP2/3 inflamma-
some (Franchi et al., 2009). It was shown previously that in sev-
eral auto-inflammatory diseases constitutive activation of NALP3
inflammasome leads to sustained local and systemic inflamma-
tion mediated by IL-1β (Goldbach-Mansky et al., 2006; Lachmann
et al., 2009b). Recently, constitutively activated inflammasome was
found in human melanoma cells (Okamoto et al., 2010). In this
study human melanoma cells from the late stage of the disease
spontaneously secrete biologically active IL-1β in the absence of
exogenous stimuli because of constitutive activation of the inflam-
masome and IL-1 receptor (IL-1R) signaling. From these findings
it can be concluded that IL-1-mediated autoinflammation con-
tributes to the development and progression of human melanoma
suggesting that inhibiting the inflammasome pathway or reducing
IL-1 activity can be a therapeutic option for melanoma patients.
The inflammasome also plays a substantial role in environmen-
tal cancer. It has been shown previously that silica and asbestos
both activate the NALP3 inflammasome resulting in an increased
IL-1β production and causing lung inflammation (Dostert et al.,
2008). Chronic exposure to asbestos has been identified as being
a high-risk factor for the development of mesothelioma implying
a crucial contribution of inflammasome-mediated inflammation
to the pathogenesis of mesothelioma. Controversely, in an animal
model of colitis-associated cancer (CAC) the NALP3 inflamma-
some was found to be protective against CAC (Allen et al., 2010).
The NALP3 inflammasome in DC obviously plays a crucial role
by linking innate and adaptive immune responses against dying
tumors (Ghiringhelli et al., 2009). Based on these observations
one can hypothesize that constitutively active NALP3 inflamma-
some as can be found in certain tumors produces large amounts
of IL-1 contributing to cancer-related inflammation and thus pro-
moting tumor growth and invasiveness, whereas activation of the
inflammasome in tumor-infiltrating immune cells might be ben-
eficial in inducing anti-tumor immunity. According to Menu and
Vince (2011), the NALP3 inflammasome can be considered as a
triple-function agent (“the good, the bad, and the ugly”) in human
malignancies.
The pleiotropic cytokine TNF plays a dual role in tumorigene-
sis. At high concentrations TNF is destructive to tumor vasculature
and induces necrosis. On the other hand, its critical role in chronic
inflammation and its tumor-promoting capacity are well docu-
mented (Lin and Yeh, 2005; Mocellin et al., 2005). An increased
expression of TNF was found in human bladder, breast, colorectal,
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FIGURE 1 | IL-1 signaling in the tumor microenvironment. IL-1 is a critical
molecule in inflammation-associated carcinogenesis produced directly by
tumor cells or cells of the tumor microenvironment. IL-1 signal transduction is
initiated by binding of either form of IL-1 to IL-1 receptor type I (IL-1RI), which
undergoes a conformational change allowing the IL-1 receptor accessory
protein (IL-1RAcP) to recognize the ligated IL-1RI. IL-1RAcP does not recognize
IL-1 but represents an essential component in the IL-1 signaling pathway
(Wesche et al., 1997b; Radons et al., 2002). The naturally occurring IL-1
receptor antagonist (IL-1Ra) also binds to IL-1RI without leading to its
activation. Ligand-mediated heterodimerization of the receptor complex leads
to recruitment of dimeric myeloid differentiation protein 88 (MyD88) via its TIR
domain (Muzio et al., 1997; Wesche et al., 1997a; Radons et al., 2003)
followed by complex formation between IRAK-4, MyD88, and IL-1RAcP and
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Inflammation and cancer
subsequent phosphorylation of IRAK-4 (Cahill and Rogers, 2008). After
recruitment of IRAK-1/Tollip to the complex, IRAK-1 is initially phosphorylated
by IRAK-4 (Born et al., 1998; Dunne and O’Neill, 2003). Subsequently, IRAK-1
(and possibly IRAK-2) becomes hyperphosphorylated and dissociates into the
cytoplasm where it binds TNF receptor-associated factor 6 (TRAF-6; Cao et al.,
1996). IRAK-1 interacts with membrane-bound TAK-binding protein 2 (TAB-2)
as well as TAK-1/TAB-1 complex (Dower and Qwarnstrom, 2003) followed by
translocation of TAB-2 from the plasma membrane to the signalosome and
subsequent partial activation of TAK-1 by TAB-2. IRAK-1, presumably as dimer
or oligomer, enables dimerization of TRAF-6 resulting in its ubiquitination and
activation. In close proximity to TAB-2, TAK-1 is partially activated followed by
complete activation through polyubiquitinated TRAF-6 (Kishimoto et al., 2000;
(continued)
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FIGURE 1 | Continued
Martin and Wesche, 2002) enabling activation of numerous signaling
cascades. Polyubiquitination of TRAF-6 obviously occurs through IRAK-2
(Keating et al., 2007). On the one hand, TAK-1 activates certain members of
the MAP kinase family leading to activation of AP-1 and ATF (Ninomiya-Tsuji
et al., 1999; O’Neill, 2000; Hefler et al., 2005; Blanco et al., 2008) the latter
augmenting NF-κB-mediated transcription via transactivation (Jefferies and
O’Neill, 2000; Cahill and Rogers, 2008). On the other hand, TAK-1
phosphorylates and activates IKK resulting in phosphorylation and
inactivation of IκBα (Wang et al., 2001). Afterward, IκBα dissociates from the
complex with NF-κB and undergoes proteasomal degradation. After
phosphorylation, NF-κB translocates to the nucleus and activates
NF-κB-dependent gene transcription (Chen and Greene, 2004). Inhibitors of
NF-κB activation are indicated that suppress the inflammatory network in
and prostate cancer as well as in leukemia and lymphoma (Balk-
will and Mantovani, 2001). TNF is also produced by cells of the
tumor microenvironment. Binding of TNF to the TNF receptor
1 (TNFR1) activates signaling cascades of NF-κB and c-Jun N-
terminal kinase (JNK) which lead to an up-regulation of several
pro-inflammatory, pro-angiogenic and invasiveness-promoting
factors, and to the induction of anti-apoptotic molecules such
as the caspase-8 inhibitor c-FLIP. Activation of NF-κB in response
to TNFR1 terminates the activity of JNK (Kamata et al., 2005).
The ubiquitin ligase Itch is a substrate of JNK that enables the
degradation of c-FLIP (Chang et al., 2006). Inhibition of JNK via
NF-κB-mediated blockage leads to an inactivation of Itch. This
prevents degradation of c-FLIP and ensures tumor cell survival.
Apart from its role in tumor initiation, TNF promotes angiogene-
sis and impairs immune surveillance by affecting T cell responses
and the activity of macrophages (Elgert et al., 1998). The tumor-
promoting role of TNF was confirmed in animal models. In the
absence of TNF mice do not develop hepatocellular carcinoma in
response to cholestatic hepatitis (Pikarsky et al., 2004). TNF and
TNFR-deficient mice were also found to be resistant to chemically
induced carcinogenesis of the skin (Arnott et al., 2004). These
findings indicate that pro-inflammatory activity of TNF functions
as a pivotal mediator in tumorigenesis (Lin and Karin, 2007).
IL-6 AND PGHS-2 (COX-2)
IL-6 is another NF-κB-regulated pleiotropic pro-inflammatory
mediator that enables tumor growth and inhibits apoptosis in a
variety of human tumors (Rose-John and Schooltink, 2007). In
contrast, IL-6 has also been reported as playing a crucial role in
terminating inflammation (Hudson et al., 2008). IL-6 signaling via
the membrane-bound receptor IL-6Ra is linked to the JAK/STAT
pathway (predominantly through activation of STAT-3) and leads
to the expression of genes encoding for anti-apoptotic cell cycle
progression molecules (Lin and Karin, 2007). In contrast, a solu-
ble form of the IL-6R can bind IL-6 with the same affinity as the
membrane-bound form and the complex of IL-6 and the soluble
IL-6R (sIL6R) can induce signaling in a process called IL-6 trans-
signaling (Peters et al., 1998). Because the IL-6R is only sparely
expressed, IL-6 trans-signaling dramatically increases the num-
ber of potential IL-6 target cells (Rose-John et al., 2006). Animal
models of inflammatory colon cancer suggest that IL-6 trans-
signaling serves as the major pro-inflammatory paradigm of IL-6
signaling under pathophysiologic conditions (Becker et al., 2004).
Frontiers in Immunology | Inflammation
Inflammation and cancer
cancer development. IL-1 signaling also involves recruitment of PI3-kinase
(PI3K) to the IL-1 receptor complex via the p85 regulatory subunit of PI3K
(Reddy et al., 1997) and subsequent activation of AKT/PKB leading to
IKK-dependent activation of NF-κB and AP-1 (Cahill and Rogers, 2008).
Receptor ligation can also activate numerous G proteins resulting in
activation of AP-1 and ATF mediated by several MAP kinases and an
IκBα-independent transactivation of NF-κB (Singh et al., 1999; Jefferies and
O’Neill, 2000). IL-1 signaling finally regulates gene expression of a great
variety of tumorigenic factors including pro-angiogenic factors (IL-8, VEGF),
growth factors (IL-6, GM-CSF), anti-apoptotic factors (Bcl-XL , c-FLIP),
invasion-promoting factors (MMP-2, MMP-7, MMP-9, uPA), inflammatory
enzymes (PGHS-2, LOX), prostaglandins, iNOS, chemokines (CCL2, CCL20,
IL-8), and pro-inflammatory cytokines (IL-1, IL-6, IL-23, TNF, TGF-β, EGF,
RANKL).
It turns out that regenerative or anti-inflammatory activities of
IL-6 are mediated by classic signaling whereas pro-inflammatory
responses of interleukin-6 are rather mediated by trans-signaling
(Rabe et al., 2008). This is important since therapeutic block-
ade of IL-6 by the neutralizing anti-IL-6 receptor monoclonal
antibody tocilizumab™ has recently been approved for the treat-
ment of inflammatory diseases. A recently performed clinical trial
revealed that IL-6 inhibition by tocilizumab retards joint damage
progression in patients with rheumatoid arthritis (Smolen et al.,
2011). Interestingly, inhibition of IL-6R-mediated signaling using
tocilizumab in a xenograft model of oral squamous cell carcinoma
(OSCC) suppressed tumor growth and angiogenesis by down-
regulating VEGF mRNA expression (Shinriki et al., 2009). Clinical
studies inclusive those mentioned above have shown that inhibi-
tion of IL-6 signaling by tocilizumab is therapeutically effective not
only in chronic inflammatory diseases such as rheumatoid arthri-
tis (Nishimoto et al., 2004), juvenile idiopathic arthritis (Yokota
et al., 2004), and Crohn’s disease (Ito et al., 2004) but also in
Castleman’s disease (Nishimoto et al., 2005). In all of these dis-
eases, tocilizumab ameliorates inflammatory manifestations, and
normalizes acute phase protein levels. Given its success in treat-
ing these diseases, tocilizumab may also prove useful in treating
IL-6-related cancers.
Elevated IL-6 levels are found in numerous tumors such as mul-
tiple myeloma (Klein et al., 1992), colorectal cancer (Chung and
Chang, 2003), gastric carcinoma (Kai et al., 2005), and Hodgkin
lymphoma (Cozen et al., 2004). Moreover, malignant ascites from
patients with epithelial ovarian cancer was found to contain high
levels of IL-6 (Offner et al., 1995). In breast cancer patients high
IL-6 concentrations induced by an IL6 gene polymorphism cor-
relate with poor prognosis (Berger, 2004). A comparison of non-
metastasizing pancreatic cancer, benign prostatic hyperplasia, and
metastasized pancreatic cancer revealed elevated levels of IL-6 in
the latter, more aggressive tumor (Weiss et al., 2011). In this study
it was shown that IL-6 leads to an increased expression of uPA and
VEGF which implies a crucial role of IL-6 in angiogenesis of pan-
creatic tumors. In OSCC lysophosphatidic acid (LPA), a bioactive
lipid with a growth factor-like activity induces the secretion of IL-6
and IL-8 in an NF-κB- and AP-1-dependent manner (Hwang et al.,
2011). Direct stimulation of human osteoblasts with IL-6 and IL-8
induced the expression of RANKL and thereby promotes osteo-
clast formation. From these findings it can be concluded that IL-6
and IL-8 derived from LPA-stimulated OSCC play a crucial role in
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osteogenesis and bone resorption. Inhibition of IL-6 signaling in
colon cancer resulted in a reduced tumor growth in mice (Becker
et al., 2004; Greten et al., 2004). Incubation of cholangiocarcinoma
cells with an anti-IL-6-neutralizing antiserum reduced AKT phos-
phorylation and down-regulated the expression of Mcl-1. This
indicates a contribution of IL-6 in the AKT-mediated survival
mechanisms (Kobayashi et al., 2005).
PGHS-2, formerly termed as COX-2, has emerged as another
pro-inflammatory mediator in tumorigenesis whose expression
is mediated by NF-κB. The expression of PGHS-2 is inducible
in response to stimuli such as mitogens, cytokines, growth fac-
tors, or hormones. PGHS-2 is the rate-limiting enzyme involved
in the conversion of arachidonic acid to prostanoids acting as
key mediators of inflammation. Aberrant or increased expression
of PGHS-2 has been shown to be involved in the pathogenesis of
breast, gastric, colorectal, lung, prostate, head/neck, and pancreatic
cancer. PGHS-2 affects cell proliferation, apoptosis, angiogenesis,
and metastasis (Lu et al., 2006; Aggarwal and Gehlot, 2009). Over-
expression of PGHS-2 results in the secretion of large amounts of
VEGF and therefore, is associated with increased tumor cell inva-
sion and poor prognosis (Raut et al., 2004; Ladetto et al., 2005).
In human basal cell carcinoma cells elevated levels of PGHS-2
led to an up-regulated expression of the anti-apoptotic mole-
cules Mcl-1 and Bcl-2, VEGF and basic fibroblast growth factor
(bFGF; Tjiu et al., 2006). In chronic inflammation, endothelial
cells express both, acute phase genes and adhesion molecules that
enable recruitment of leukocytes to the site of tissue damage.
Moreover, an enhanced production of prostaglandins mediated
by PGHS-2 augments vasopermeability leading to a more pro-
nounced recruitment of leukocytes (Jura et al., 2005). Leukocytes
are the main source of RNS and ROS acting as chemical effectors
in inflammation-driven carcinogenesis (Kundu and Surh, 2008).
We identified a constitutively enhanced expression of PGHS-2 in
human pancreatic adenocarcinoma cells that is further increased
in the presence of IL-1 (Bauer et al., 2009; Hoffmann et al., 2011).
The constitutive production of PGHS-2 and its key product PGE2
in the microenvironment of pancreatic carcinomas accounts for
an enhanced malignancy of pancreatic tumor cells which is caused
by inhibition of apoptosis, increase in cell proliferation, induction
of angiogenesis, and invasion of malignant cells into surrounding
tissue (Merati et al., 2001; Kong et al., 2002; Garcea et al., 2005).
PGHS-2 also induces the expression of MMP-2 (Surh et al., 2001;
Sansone et al., 2009; Wang et al., 2009b) and pro-inflammatory IL-
6 and IL-1 via PGE2 (Takahashi et al., 2008). PGHS-2-mediated
effects on growth, angiogenesis, invasiveness, and metastasis are
augmented by the IL-1-induced up-regulation of the enzyme by
forcing the progression of a positive amplification loop triggered
by PGE2 and IL-6. Of note, it was demonstrated that PGE2 con-
tributes to cancer progression by inhibiting DC differentiation
and function, acting paradoxically as an immunosuppressive fac-
tor (Muthuswamy et al., 2010; Stock et al., 2011). In cervical cancer,
PGE2 was found to induce a cytokine production profile and phe-
notypical features of tolerogenic DC suggesting that the altered
expression of PGE2 might promote carcinogenesis by favoring
(pre)cancer immunotolerance (Herfs et al., 2009). In addition,
IL-6 derived from tumor cells or cells of the tumor microenviron-
ment was shown to polarize DC toward immune tolerance through
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Inflammation and cancer
the induction of STAT-3 activation (Alshamsan, 2011). Therefore,
tumor-induced p-STAT-3 in DC can be seen as a promising target
for colon cancer immunotherapy. In this context, knocking-down
the IL-6 receptor α-chain of DC vaccines significantly enhanced
the frequency of tumor-specific CD8+ CTL-producing effector
molecules such as IFN-γ, TNF, FasL, perforin, and granzyme B, and
generated more CD8+ memory T cells, leading to the substantially
prolonged survival of cytotoxic lymphocytes (Tc1) tumor-bearing
mice (Hwang et al., 2010).
Most of the PGHS-2-induced effects are mediated through its
product PGE2 (Yoshimatsu et al., 2001a,b). Thus, down-regulation
of prostaglandins in tumor tissues by PGHS-2 inhibition blocks
several neoplastic pathways leading to the suppression of tumor
growth (Maier et al., 2004). In this context, PGHS-2 inhibitors
hold promise for cancer chemoprevention. Among them, the
non-steroidal anti-inflammatory drug (NSAID) celecoxib con-
stitutes a potent and specific inhibitor of the inducible human
PGHS-2. Celecoxib interferes with tumor initiation and tumor
cell growth in vitro and in vivo. Preclinical studies demonstrate
promising anti-cancer effects of celecoxib in colorectal, pancreatic
as well as head and neck carcinomas. Additionally, celecoxib was
found to increase tumor cell sensitivity toward radiochemotherapy
(reviewed by Jendrossek, 2011). Celecoxib has also been found to
impair tissue expression of VEGF, tumor angiogenesis, and metas-
tasis in an experimental model of pancreatic cancer (Wei et al.,
2004). Thus, modulation of PGHS-2 expression may be a promis-
ing approach in cancer therapy (Jimeno et al., 2006). However,
due to the high toxicity of PGHS-2 inhibitors, the development of
novel components is necessary (Spektor and Fuster, 2005; Lee et al.,
2007). Randomized clinical trials and meta-analyses reported on
an increased risk for cardiovascular diseases in patients receiving
long-term treatment with PGHS-2 inhibitors. These cardiovas-
cular adverse effects include myocardial infarction, stroke, and
cardiovascular death/heart failure (summarized by Trelle et al.,
2011). This increased rate of life-threatening cardiovascular side
effects led to the withdrawal of the PGHS-2 inhibitors valde-
coxib and rofecoxib from the market that had been approved by
the United States Food and Drug Association. A patient-pooled
analysis of adjudicated data from 7,950 patients in six placebo-
controlled trials demonstrated a dose regimen-related increase in
the risk of serious cardiovascular events after a daily administra-
tion of 400 and 800 mg celecoxib (Solomon et al., 2008). Although
long-term treatment with high-dose celecoxib can enhance the
risk for cardiovascular diseases, the drug is still used at lower doses
in the United States since it is less toxic compared to other PGHS-2
inhibitors (Solomon et al., 2008; Trelle et al., 2011).
A novel approach to overcome the limitations associated with
the toxicity of PGHS-2 inhibitors is to combine chemical PGHS-
2 inhibitors at low doses with naturally occurring compounds
such as the catechin EGCG which is a promising chemopreven-
tive agent derived from green tea (summarized by Cerella et al.,
2010). Our group investigated the effects of a combinatorial treat-
ment with celecoxib and EGCG on the expression of IL-1-induced
tumorigenic factors in human pancreatic adenocarcinoma cells.
We found that the combined administration of celecoxib and
EGCG can induce synergistic cancer preventive effects in pan-
creatic cancer cells by down-regulating tumorigenic factors and
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Multhoff et al.
inducing apoptosis (Härdtner et al., 2009). Previous investiga-
tions of our group and others revealed anti-proliferative and
apoptosis-inducing effects of EGCG and celecoxib in pancreatic
cancer cells (Chen and Zhang, 2007; Inaba et al., 2008; Xu et al.,
2008; Hoffmann et al., 2011). The anti-proliferative properties of
NSAID such as celecoxib are related to effects on the cell cycle
(Xiong, 2004) including changes in gene expression that favor
cell cycle arrest (Yip-Schneider et al., 2001; Tseng et al., 2002).
Interestingly, several studies revealed an anti-proliferative effect
of PGHS-2-selective inhibitors not only in PGHS-2-positive but
also in PGHS-2-negative pancreatic tumor cells implying that the
inhibitory action of NSAID on cell proliferation can affect both,
PGHS-2-dependent and -independent pathways (Molina et al.,
1999; Yip-Schneider et al., 2001). Numerous investigations also
documented an apoptosis-inducing potential of NSAID (Maier
et al., 2004; Suganuma et al., 2011). Celecoxib targets several
proteins distinct from PGHS-2 that are involved in the control
of cell survival and cell death including the anti-apoptotic pro-
teins survivin, Mcl-1, and Bcl-2 (Sakoguchi-Okada et al., 2007;
Rudner et al., 2010). Further, PGHS-2-independent molecular
targets of celecoxib comprise the survival kinase AKT/PKB and
its up-stream regulator 3-phosphoinositide-dependent kinase-1
(PDK-1; Belham et al., 1999; Kulp et al., 2004), cyclin-dependent
kinase inhibitors, and cyclins (Grosch et al., 2006), as well as
the sarcoplasmic/endoplasmic reticulum calcium ATPase SERCA
(Johnson et al., 2002). By counteracting these molecules celecoxib
interferes with the activation status of caspases and finally induces
apoptosis.
EGCG-mediated effects on apoptosis include caspase-3/-9 acti-
vation, PARP cleavage, Bax oligomerization, mitochondrial mem-
brane depolarization, direct interaction with anti-apoptotic mem-
bers of the Bcl-2 family as well as NF-κB inhibition (Lambert
et al., 2005; Shimizu et al., 2005; Inaba et al., 2008). Celecoxib
is reported to interfere, among others, with the NF-κB signaling
pathway (Niederberger et al., 2001; Shirode and Sylvester, 2010)
providing the basis for the synergism with EGCG. Based on these
findings one can hypothesize that celecoxib in combination with
EGCG may promote apoptosis directly or indirectly thus altering
the cellular death threshold in tumor cells (Jendrossek, 2011). In
previous studies EGCG has been shown to synergistically enhance
the effects of TRAIL (Siddiqui et al., 2008) and PGHS-2 inhibitors
NS-398 (Adhami et al., 2007) and celecoxib (Basu and Haldar,
2009). In a human lung (Suganuma et al., 2011) and prostate can-
cer (Adhami et al., 2007) model the combination of celecoxib and
EGCG increased tumor cell apoptosis and decreased inflamma-
tion. Other natural compounds affecting the PGHS-2 expression
include the non-flavonoid polyphenols curcumin from turmeric
Curcuma longa, resveratrol from red wine, isoflavone genistein
from lupin as well as omega-3 fatty acids from oily fish flaxseeds.
Such a combinatory administration might have future clinical
implications with respect to an adjuvant therapy in cancer patients,
since it might reduce the adverse effects of high-dose celecoxib as
a monotherapy.
INTERACTIONS OF NF-κB AND STAT-3
Both, STAT-3 and NF-κB are crucial for cancer-related inflam-
mation. NF-κB does not only mediate tumorigenesis but also
Frontiers in Immunology | Inflammation
Inflammation and cancer
exerts anti-tumorigenic effects in tumor cells and in the tumor
microenvironment (for a review see Ben-Neriah and Karin,
2011). Evidence for a positive association of NF-κB activation
with tumor-associated inflammation came from colitis-associated
colon cancer (Greten et al., 2004; Pikarsky et al., 2004) and
hepatitis-associated hepatocellular carcinoma (Pikarsky et al.,
2004). Colitis-associated colon cancer represents a classical exam-
ple for an inflammation-triggered malignancy. NF-κB activation
in intestinal epithelial cells of this cancer model was found to
enhance the survival of pre-malignant progenitor cells by inducing
anti-apoptotic Bcl-XL (Greten et al., 2004; Pikarsky et al., 2004).
NF-κB activation in cancer seems to be related, at least in part,
by mutations in components of the signaling cascade or effects of
inflammatory factors in the tumor microenvironment that accu-
mulate after NF-κB activation (Karin et al., 2002). Transcriptional
activation of NF-κB leads to the induction of pro-inflammatory
cytokines (e.g., IL-1, IL-6, TNF), chemokines (IL-8), PGHS-2,
MMP, and adhesion molecules (ICAM-1, VCAM-1). The presence
of constitutively active NF-κB in most tumors correlate with a poor
clinical outcome (Weichert et al., 2007). Moreover, most chemo-
preventive agents including nutraceuticals derived from different
sources have the potential to suppress constitutive and inducible
NF-κB activation pathways (Aggarwal and Gehlot, 2009) in order
to block chronic inflammation.
Whilst NF-κB signaling contributes to both, inflammation-
driven carcinogenesis and anti-tumor immunity, STAT-3
induces cancer-promoting inflammation and restrains anti-tumor
immune responses by counteracting NF-κB-induced expression of
anti-tumor Th1 cytokines (IL-12, IFN-γ; Kortylewski et al., 2005;
Yu et al., 2007). Furthermore, STAT-3 contributes to the expansion
and development of Treg and Th17 cells (Wang et al., 2009a; Wu
et al., 2009). STAT-3 also induces the expression of tumorigenic
mediators (cytokines, pro-angiogenic, and growth factors) and
their corresponding receptors that in turn activate a STAT-3 medi-
ated immunoregulatory circuit in the tumor microenvironment
(Yu et al., 2007). Thus, the constitutive activation of STAT-3, does
not only promote cancer-related inflammation but also suppresses
anti-tumor immune responses (Yu et al., 2009).
As already mentioned, the association of cancer with chronic
inflammation is related to intrinsic and extrinsic pathways, both
leading to activation of NF-κB and STAT-3. Similarly to NF-κB,
constitutively active STAT-3 is found in breast, ovarian, prostate,
and brain tumors, leukemia, lymphoma, and multiple myeloma.
STAT-3 activation results in the modulation of the expression
of numerous genes that are crucial for maintaining/amplifying
tumor-associated inflammation and promoting tumor growth
and progression (Yu et al., 2009). The NF-κB family comprises
homo- and heterodimeric transcription factors consisting of RelA,
c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-
κB2 (p52 and its precursor p100) with RelA-p50 as being the
most prominent NF-κB transcription factor (Vallabhapurapu and
Karin, 2009). Physiologically, NF-κB is sequestered in the cytosol
by its inhibitory component, IκBα. Upon phosphorylation by the
IκB kinase complex (IKK), IκBα is degraded in an ubiquitin-
dependent manner in the proteasome. Then NF-κB translocates
into the nucleus where predominantly RelA-p50 up-regulates the
expression of Th1 immunostimulatory genes (IL-12, CD40, CD80)
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Multhoff et al.
that are important for the control of microbial infections and
tumor cells (Yu et al., 2007, 2009). STAT-3 opposes the anti-tumor
immune responses mediated by NF-κB within a cell. On the one
hand, STAT-3 is able to inhibit IKK during acute inflammation
and thus attenuates Th1 immune responses (Lee et al., 2009). On
the other hand, STAT-3 prolongs the nuclear retention of RelA
during oncogenic and chronic inflammation by acting as a co-
transcription factor for RelA thus contributing to the persistent
activation of NF-κB during chronic inflammation and the malig-
nant process (Yu et al., 2009). It has been shown previously that
STAT-3 promotes nuclear localization of RelA by acetyltransferase
p300-mediated acetylation affecting the NF-κB/IκBα interaction
and avoiding its nuclear export (Chen and Greene, 2004). Since
STAT-3 is a prerequisite for p300-mediated acetylation of RelA,
constitutive activity of RelA in tumors requires continuous STAT-
3 signaling (Lee et al., 2009). Accordingly, increased STAT-3 activity
found in tumors preferentially leads to an association of NF-κB
with STAT-3 via p300. Due to the NF-κB activating capacity of
STAT-3 in malignancies constitutive activity of STAT-3 found in
tumors preferentially requires RelA (Yu et al., 2009). As stated
by the authors, this reciprocal relationship is related to the fact
that numerous RelA-encoded target gene products function as
STAT-3 activators (e.g., IL-6, IL-11, IL-17, IL-21, IL-23, PGHS-2).
Remarkably, expression of IL-6, IL-17, IL-23, and PGHS-2 (all of
them activating STAT-3) depends on STAT-3 as co-transcription
factor for NF-κB. As a consequence, STAT-3 and NF-κB interact at
multiple levels and thereby boost tumor-associated inflammation.
HEAT SHOCK PROTEINS AND TUMORIGENESIS
Heat shock proteins (HSP) are highly conserved proteins expressed
in a wide range of species where they inhabit nearly all cel-
lular and subcellular compartments. Environmental stress (e.g.,
heat, hypoxia, bacterial infections, heavy metals, oxidative stress,
inflammation) as well as physiological processes (differentiation,
proliferation, maturation) result in an increased HSP synthesis
(Lindquist and Craig, 1988; DeNagel and Pierce, 1992). Intra-
cellular residing HSP protect cells against lethal damage induced
by environmental stress, and support folding and transport of
newly produced polypeptides and aberrant proteins (Hartl, 1996).
Depending on their intra-/extracellular localization HSP mediate
different functions. On the one hand, up-regulated intracellu-
lar HSP levels protect tumor cells from lethal damage induced
by environmental stress. On the other hand, membrane-bound
and extracellular residing HSP with molecular weights of 70 and
90 kDa were identified as key regulators of the host’s immune
system.
A variety of HSP were found on the plasma membrane of tumor
cell lines as determined by selective cell surface protein profil-
ing (Shin et al., 2003). These findings were confirmed by a broad
screening program of human tumor biopsies in our laboratory
using cmHsp70.1 mAb (Stangl et al., 2011). Phenotypic analyses
revealed that Hsp70, the major stress-inducible member of the
HSP70 group, is found on the plasma membrane in 50–70% of
colon, lung, pancreas, mammary, head and neck, lung, and uro-
genital carcinomas (Multhoff et al., 1995a,b; Chen et al., 2002).
Metastases exhibit an elevated Hsp70 membrane density com-
pared to primary tumors in humans (unpublished observation).
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Inflammation and cancer
These data were confirmed in a xenograft tumor mouse model.
After orthotopic injection of human tumor cells into immuno-
deficient animals the cell surface density of Hsp70 was greater on
metastases than on primary tumors (Multhoff et al., 2000; Stangl
et al., 2006). Interestingly, the corresponding normal tissue of the
mice was always found to be membrane Hsp70-negative (Stangl
et al., 2011). These findings might be explained by the fact that
membrane Hsp70 might facilitate metastases, support adherence
of tumor cells to endothelial cells and organs, or might confer
resistance to an unfavorable milieu during metastasis. In line with
these findings we could show that overall survival of patients with
membrane Hsp70-positive squamous cell carcinomas of the lung
and lower rectal carcinomas was significantly reduced compared
to those patients with membrane Hsp70-negative tumors (Pfister
et al., 2007). Apart from solid tumors also bone marrow samples of
patients suffering from acute (AML) and chronic (CML) myeloid
leukemia are frequently membrane Hsp70-positive (Gehrmann
et al., 2003). Quantitative analysis revealed that ∼15–20% of the
total Hsp70 is present in tumor cell membranes (Gehrmann et al.,
2008). The anchorage of Hsp70 within the plasma membrane is
most likely mediated by the tumor-specific glycosphingolipid Gb3
(Gehrmann et al., 2008). This led us to the hypothesis that mem-
brane Hsp70 might provide an ideal tumor-specific molecule for
a targeted immunotherapeutic approach.
Even in the absence of immunogenic peptides, Hsp70, or a
peptide derived thereof in combination with pro-inflammatory
cytokines such as IL-2 and IL-15 has the capacity to stimulate the
cytolytic activity of NK cells against membrane Hsp70-positive
tumor cells (Multhoff et al., 1997, 2001). The mechanism of tumor
cell killing has been identified as perforin-independent granzyme
B-mediated apoptosis (Gross et al., 2003b). Granzyme B derived
from activated NK cells specifically binds to membrane Hsp70 on
tumor cells and following Hsp70-mediated endocytosis, apoptosis
is induced (Gross et al., 2003a,b). Hsp70 also has been detected
on tumor-derived exosomes of membrane Hsp70-positive tumors
(Gastpar et al., 2005). These data suggest that NK cells might
be attracted to membrane Hsp70-positive tumors in vivo via the
secretion of Hsp70 surface-positive exosomes. Incubation of NK
cells with Hsp70 protein or a 14mer-peptide derived from the C-
terminus of Hsp70 is accompanied by an up-regulation of activat-
ing receptors on NK cells such as CD94/NKG2C, NKG2D, NKp30,
NKp44, and NKp46 (Gross et al., 2003b,c). Hsp70 membrane-
positive tumors are thus efficiently eliminated by NK cells that
had been pre-stimulated with low dose IL-2 plus Hsp70 peptide
(Multhoff et al., 1999). Adoptive transfer of these TKD-stimulated
NK cells in tumor-bearing mice revealed identical results in vivo
(Botzler et al., 1998; Multhoff et al., 2000; Moser et al., 2002). It
is known that IL-2-activated NK cells are able to induce regres-
sion of established lung and liver tumors (Schwarz et al., 1989;
Yasumura et al., 1994; Vujanovic et al., 1995; Whiteside et al.,
1998). Our group identified a specific migratory capacity of NK
cells toward Hsp70-postive tumor cells and supernatants derived
thereof. The same effect could be observed for the Hsp70 peptide
TKD (Gastpar et al., 2004). From these results we speculated that
killing of Hsp70-positive tumors in vivo might be related to an
enhanced migratory and cytolytic capacity of pre-activated NK
cells.
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Multhoff et al.
The rapid induction of HSP in response to environmental
stress is based on a variety of genetic and biochemical processes
referred to as the heat shock response (HSR; Shamovsky and
Nudler, 2008). The link between HSR and cancer development
has been emerging since more than 20 years. HSR is regulated
mainly at the transcription level by heat shock factors (HSF).
Among them, HSF-1 is considered as being the key transcrip-
tion factor of stress-inducible HSP (Pirkkala et al., 2001; Akerfelt
et al., 2010). As a consequence, HSP are over-expressed in a wide
spectrum of human malignancies contributing to tumor growth,
differentiation, invasiveness, and metastasis and being associated
with poor prognosis in certain cancer types (Ciocca and Calder-
wood, 2005). HSP over-expression in tumor cells plays a pivotal
role in tumorigenesis by inhibiting apoptosis and senescence. In
breast cancer, transformation-induced activation of HSF-1 results
in an up-regulated expression of Hsp27 and Hsp70 which in turn
results in protection against apoptosis (Calderwood, 2010). HSF-
1 also triggers expression of Hsp90, an essential factor in tumor
growth due to its ability to chaperone a variety of oncogenic sig-
naling proteins including Her-2/neu and c-Src (Kamal et al., 2003;
Neckers and Lee, 2003; Calderwood, 2010). Several studies have
shown that Her-2/neu (c-ErbB-2) is amplified and over-expressed
in many tumors such as breast, ovarian, and gastric adenocarci-
noma (Hynes and Stern, 1994). Since HSP over-expression also
protects from drug-related apoptosis (Khaleque et al., 2005), these
mechanisms highlight the role of HSP in tumor progression and
therapy resistance.
Recent studies indicate an involvement of HSP such as
Hsp70/Hsp72 and Hsp90 in the recognition of PAMP by bind-
ing to TLR-4 within lipid rafts (Triantafilou and Triantafilou,
2004; Wheeler et al., 2009). Since extracellular residing Hsp70
acts as a danger signal for the immune system (Matzinger, 1998),
this stress protein has been added to the list of “alarmins.”
Endogenous alarmins and exogenous PAMP both comprise the
group of danger-associated molecular patterns (DAMP; Bianchi,
2007). Hsp70, added exogenously to cells stimulates the pro-
duction of pro-inflammatory cytokines TNF, IL-1β, and IL-6 by
antigen presenting cells (Asea et al., 2000a,b, 2002). Extracellu-
lar Hsp70 has also been found to induce IL-8 production in
human bronchial epithelial cells (Chase et al., 2007). In vitro co-
culturing of colon tumor cell spheroids with normal cells caused
a significant tumor grade-dependent increase in IL-6 produc-
tion thereby altering Hsp70 expression (Paduch et al., 2009).
From these observations it can be concluded that Hsp70 may
enhance the impact of tumorigenic mediators in the tumor
microenvironment.
CONCLUDING REMARKS
Cancer-related inflammation has emerged as one of the hall-
marks of cancer (Hanahan and Weinberg, 2011). In the last
two decades, several tumorigenic factors have been identified
as being implicated in inflammation-associated carcinogenesis.
These factors are released by tumor cells or cells of the tumor
microenvironment such as stromal cells, endothelial cells, or
host infiltrating cells, respectively, and include pro-inflammatory
cytokines, pro-angiogenic and growth-promoting factors,
anti-apoptotic and invasion-promoting factors, inflammatory
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Inflammation and cancer
enzymes, prostaglandins, iNOS as well as chemokines. Among
them, IL-1, TNF, and IL-6 act as crucial mediators of
inflammation-driven tumorigenesis forming an inflammatory
network in cancer as outlined in Figure 2. These mediators activate
the key transcription factors in tumor-associated inflammation:
NF-κB, STAT-3, and HIF-1 impacting any stage of tumorigen-
esis such as initiation, promotion as well as progression, and
metastasis. It is noteworthy that NF-κB might be the central
player in tumorigenesis. NF-κB is activated by a great vari-
ety of lifestyle-related factors including infectious agents, irra-
diation, environmental stimuli, tobacco, stress, dietary agents,
obesity, and alcohol accounting for almost 95% of all cancers
(Aggarwal and Gehlot, 2009). Modern anti-tumor therapies thus
aim to suppress NF-κB activation. Most of the chemopreventive
agents have been found as being able to suppress NF-κB acti-
vation like the selective PGHS-2 inhibitor celecoxib. Moreover,
lifestyle-related agents derived from different sources including
fruits, legumes, vegetables, grains, spices, and exercise are also
able to inhibit NF-κB leading to suppression of the inflamma-
tory network (Aggarwal and Gehlot, 2009). Clinical and pre-
clinical studies are conducted to suppress the inflammatory net-
work by the use of, e.g., steroids (dexamethasone, prednisolone),
TNF inhibitors (thalidomide = thalomid™, anti-TNF antibod-
ies such as infliximab = remicade™, etanercept = enbrel™, adal-
imumab = humira™), IL-1 inhibitors (anakinra™ = IL-1 recep-
tor antagonist), PGHS-2 inhibitors (celecoxib), NF-κB inhibitors
(curcumin, EGCG, piperazine), and RANKL inhibitors (deno-
sumab™ = fully human monoclonal anti-RANKL antibody). A
promising approach in cancer therapy also might be targeting
HSP, because up-regulated Hsp90 and Hsp70 in cancer cells have
FIGURE 2 | Interactions of inflammatory mediators in tumor cells.
Schematical simplified representation of the complex intracellular signaling
network in cancer. Among the tumorigenic factors produced by tumor cells
or cells of the tumor microenvironment, IL-1, TNF, and IL-6 act as crucial
mediators of inflammation-driven tumorigenesis. In particular IL-1 and TNF
are major pleiotropic cytokines involved in tumor/host interactions.
Nevertheless, these cytokines function as autocrine growth factors and
modulate the expression of several tumorigenic factors at any stage of
tumorigenesis not only affecting proliferation, migration, and survival of
tumor cells but also angiogenesis, invasiveness, metastasis as well as
chemoresistance of tumors.
January 2012 | Volume 2 | Article 98 | 10
Multhoff et al. Inflammation and cancer

been recognized as important drug targets and are under intensive
studies in recent years. HSP are currently being targeted in the ther-
apy of breast cancer and other carcinomas and effective drugs for
Hsp90 (e.g., geldanamycin and its analogs) have been synthesized
and evaluated in clinical trials (Calderwood and Gong, 2011; Kim
and Kim, 2011). HSP vaccines have been intensively studied in the
preceding two decades, proving to be safe and effective in treating
a number of malignancies (Murshid et al., 2011). However, thera-
peutical approaches that completely block one tumorigenic factor
should be avoided, since it might also interfere with the physio-
logical anti-tumor immune response and could therefore prove
to be harmful. Instead, partial inhibition of numerous factors is
preferred resulting in an enhanced efficacy thereby being less toxic
to the patient.
ACKNOWLEDGMENTS
The authors want to thank Anett Lange for excellent edi-
torial assistance. The work was supported by the Deutsche
Forschungsgemeinschaft (DFG) SFB-824, DFG-Cluster of Excel-
lence: Munich Advanced Photonics, Bundesministerium für Bil-
dung und Forschung (BMBF) MOBITUM (01EZ0826) Innovative
Therapies (01GU0823), m4 – Personalized Medicine and Targeted
Therapies (01EX1021C), Kompetenzverbund Strahlenforschung
(03NUK007E), and multimmune GmbH.

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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 25 October 2011; accepted: 28
December 2011; published online: 12 Jan-
uary 2012.
Citation: Multhoff G, Molls M and
Radons J (2012) Chronic inflammation
in cancer development. Front. Immun.
2:98. doi: 10.3389/fimmu.2011.00098
This article was submitted to Frontiers in
Inflammation, a specialty of Frontiers in
Immunology.
Copyright © 2012 Multhoff, Molls and
Radons. This is an open-access article
distributed under the terms of the Cre-
ative Commons Attribution Non Com-
mercial License, which permits non-
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